WO2016126682A1 - Méthodes de contrôle de régimes thérapeutiques - Google Patents

Méthodes de contrôle de régimes thérapeutiques Download PDF

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Publication number
WO2016126682A1
WO2016126682A1 PCT/US2016/016133 US2016016133W WO2016126682A1 WO 2016126682 A1 WO2016126682 A1 WO 2016126682A1 US 2016016133 W US2016016133 W US 2016016133W WO 2016126682 A1 WO2016126682 A1 WO 2016126682A1
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Prior art keywords
therapeutic
subject
level
cancer
heparin
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PCT/US2016/016133
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English (en)
Inventor
He Zhou
Takashi Kei Kishimoto
Birgit Schultes
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Momenta Pharmaceuticals, Inc.
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Publication of WO2016126682A1 publication Critical patent/WO2016126682A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/475—Assays involving growth factors
    • G01N2333/4753—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • This disclosure relates to methods of controlling therapeutic regimens using HGF biomarkers are disclosed herein.
  • a therapeutic regimen for a solid tumor cancer in a subject comprising: identifying a subject that is receiving a therapeutic regimen for a solid tumor cancer; receiving information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; using the information to select an action for the therapeutic regimen; and implementing the action in the subject.
  • HGF hepatocyte growth factor
  • the action is modifying the therapeutic regimen to increase or decrease the amount of at least one therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of at least one therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of at least one therapeutic in the regimen administered to the subject. In some
  • the action is maintaining the therapeutic regimen to maintain the amount of time between doses of at least one therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration at least one therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of at least one therapeutic in the regimen administered to the subject.
  • the at least one therapeutic is a heparin. In some embodiments, the at least one therapeutic is a LMWH (e.g., as described herein). In some embodiments, the at least one therapeutic is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab- paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject. In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • methods of controlling a therapeutic regimen comprising a heparin therapeutic in a subject with a cancer comprising: identifying a subject that is receiving a therapeutic regimen comprising a heparin therapeutic for a cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; using the information to select an action for the therapeutic regimen; and implementing the action in the subject.
  • the action is modifying the therapeutic regimen to increase or decrease the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is maintaining the therapeutic regimen to maintain the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of the heparin therapeutic in the regimen administered to the subject.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject.In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is receiving a therapeutic regimen comprising a heparin therapeutic for a cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is within a predetermined range, then performing a first action with respect to the heparin therapeutic; or if the level of the HGF provided by the information is within a predetermined range, then performing a first action and a second action which distinct from the first action, with respect to the heparin therapeutic.
  • the action is modifying the therapeutic regimen to increase or decrease the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is maintaining the therapeutic regimen to maintain the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of the heparin therapeutic in the regimen administered to the subject.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject.In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is receiving a therapeutic regimen comprising a heparin therapeutic for a cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is below a predetermined level, then modifying the therapeutic regimen to increase the amount of the heparin therapeutic administered to the subject.
  • the action is modifying the therapeutic regimen to increase or decrease the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is maintaining the therapeutic regimen to maintain the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of the heparin therapeutic in the regimen administered to the subject.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject.In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is receiving a therapeutic regimen comprising a heparin therapeutic for a cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is above a predetermined level, then modifying the therapeutic regimen to decrease the amount of the heparin therapeutic administered to the subject.
  • the action is modifying the therapeutic regimen to increase or decrease the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is maintaining the therapeutic regimen to maintain the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of the heparin therapeutic in the regimen administered to the subject.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject.In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising: instructing or requesting an entity use an assay to provide information providing a level of HGF in a subject that is receiving a therapeutic regimen for a heparin therapeutic for a cancer; using the information to select an action for the therapeutic regimen; and implementing the action in the subject.
  • the action is modifying the therapeutic regimen to increase or decrease the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is maintaining the therapeutic regimen to maintain the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of the heparin therapeutic in the regimen administered to the subject.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject.In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a solid tumor cancer in a subject comprising identifying a subject that is a candidate for treatment with a therapeutic regimen for a solid tumor cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; using the information to select an action for the therapeutic regimen; and implementing the action in the subject.
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is a candidate for treatment with a therapeutic regimen comprising a heparin therapeutic for a cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; using the information to select an action for the therapeutic regimen; and implementing the action in the subject.
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is a candidate for treatment with a therapeutic regimen comprising a heparin therapeutic for a cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is within a predetermined range, then performing a first action with respect to the heparin therapeutic; or if the level of the HGF provided by the information is within a predetermined range, then performing a second action, distinct from the first action, with respect to the heparin therapeutic.
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is a candidate for treatment with a therapeutic regimen comprising a heparin therapeutic for a cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is below a predetermined level, then instructing modification of the therapeutic regimen to increase the amount of the heparin therapeutic administered to the subject.
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic. In some embodiments, the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel.
  • the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is a candidate for treatment with a therapeutic regimen comprising a heparin therapeutic for a cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is above a predetermined level, then modifying the therapeutic regimen to decrease the amount of the heparin therapeutic administered to the subject.
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a solid tumor cancer in a subject comprising: identifying a subject that is receiving a therapeutic regimen for a solid tumor cancer; providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; using the information to inform an action for the therapeutic regimen; and instructing implementation of the action in the subject, wherein the action is implemented.
  • HGF hepatocyte growth factor
  • the action is modifying the therapeutic regimen to increase or decrease the amount of at least one therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of at least one therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of at least one therapeutic in the regimen administered to the subject. In some embodiments, the action is maintaining the therapeutic regimen to maintain the amount of time between doses of at least one therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration at least one therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of at least one therapeutic in the regimen administered to the subject.
  • the at least one therapeutic is a heparin. In some embodiments, the at least one therapeutic is a LMWH (e.g., as described herein). In some embodiments, the at least one therapeutic is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab- paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel.
  • the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject. In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer. In some embodiment, the level of HGF is determined in a biological sample obtained from the subject. In some embodiments, the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • an enzyme-linked immunosorbent assay ELISA
  • an aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen comprising a heparin therapeutic in a subject with a cancer, the method comprising:
  • identifying a subject that is receiving a therapeutic regimen comprising a heparin therapeutic for a cancer providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; using the information to inform an action for the therapeutic regimen; and instructing implementation of the action in the subject, wherein the action is implemented.
  • HGF hepatocyte growth factor
  • the action is modifying the therapeutic regimen to increase or decrease the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is maintaining the therapeutic regimen to maintain the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of the heparin therapeutic in the regimen administered to the subject.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject.In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is receiving a therapeutic regimen comprising a heparin therapeutic for a cancer; providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen;
  • HGF hepatocyte growth factor
  • the level of the HGF provided by the information is within a predetermined range, then using the information to inform a first action with respect to the heparin therapeutic; or if the level of the HGF provided by the information is within a predetermined range, then using the information to inform a first action and a second action which distinct from the first action, with respect to the heparin therapeutic; and instructing implementation of the action in the subject, wherein the action is implemented.
  • the action is modifying the therapeutic regimen to increase or decrease the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of the heparin therapeutic in the regimen administered to the subject. In some
  • the action is maintaining the therapeutic regimen to maintain the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of the heparin therapeutic in the regimen administered to the subject.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject.In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • described herein are methods of controlling a therapeutic regimen for a heparin therapeutic in a subject with a cancer, the method comprising identifying a subject that is receiving a therapeutic regimen comprising a heparin therapeutic for a cancer; providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; if the level of the HGF provided by the information is below a predetermined level, then instructing modification of the therapeutic regimen to increase the amount of the heparin therapeutic administered to the subject.
  • HGF hepatocyte growth factor
  • described herein are methods of controlling a therapeutic regimen for a heparin therapeutic in a subject with a cancer, the method comprising
  • identifying a subject that is receiving a therapeutic regimen comprising a heparin therapeutic for a cancer providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is above a predetermined level, then instructing modification of the therapeutic regimen to decrease the amount of the heparin therapeutic administered to the subject.
  • HGF hepatocyte growth factor
  • the action is modifying the therapeutic regimen to increase or decrease the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is modifying the therapeutic regimen to increase or decrease the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is sustaining the therapeutic regimen to maintain the amount of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is maintaining the therapeutic regimen to maintain the amount of time between doses of the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is discontinuing administration the heparin therapeutic in the regimen administered to the subject. In some embodiments, the action is withholding one or more dose of the heparin therapeutic in the regimen administered to the subject.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • the information meets the first predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level. In some embodiments, the first action is modifying the therapeutic regimen to maintain or decrease the amount of the therapeutic administered to the subject.In some embodiments, the second action is modifying the therapeutic regimen to increase the amount of the therapeutic administered to the subject.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a solid tumor cancer in a subject comprising identifying a subject that is a candidate for treatment with a therapeutic regimen for a solid tumor cancer; providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; and using the information to select an action for the therapeutic regimen.
  • HGF hepatocyte growth factor
  • the action is administering the heparin therapeutic at a specific dose.
  • the action is administering the heparin therapeutic at a dose within a predetermined range.
  • the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is a candidate for treatment with a therapeutic regimen comprising a heparin therapeutic for a cancer; providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; and using the information to select an action for the therapeutic regimen.
  • HGF hepatocyte growth factor
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is a candidate for treatment with a therapeutic regimen comprising a heparin therapeutic for a cancer; providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is within a predetermined range, then instructing a first action with respect to the heparin therapeutic; or if the level of the HGF provided by the information is within a predetermined range, then instructing a second action, distinct from the first action, with respect to the heparin therapeutic.
  • HGF hepatocyte growth factor
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is a candidate for treatment with a therapeutic regimen comprising a heparin therapeutic for a cancer; providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is below a predetermined level, then instructing modification of the therapeutic regimen to increase the amount of the heparin therapeutic administered to the subject.
  • HGF hepatocyte growth factor
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer. In some embodiment, the level of HGF is determined in a biological sample obtained from the subject. In some embodiments, the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • an enzyme-linked immunosorbent assay ELISA
  • an aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is a candidate for treatment with a therapeutic regimen comprising a heparin therapeutic for a cancer; receiving information providing a level of HGF in the subject, wherein the level of HGF is a signal of activity of one or more heparin therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is above a predetermined level, then modifying the therapeutic regimen to decrease the amount of the heparin therapeutic administered to the subject.
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • a therapeutic regimen for a heparin therapeutic in a subject with a cancer comprising identifying a subject that is a candidate for treatment with a therapeutic regimen comprising a heparin therapeutic for a cancer; providing information providing a level of hepatocyte growth factor (HGF) in the subject, wherein the level of HGF is a signal of activity of one or more therapeutics in the therapeutic regimen; and if the level of the HGF provided by the information is below a predetermined level, then instructing modification of the therapeutic regimen to increase the amount of the heparin therapeutic administered to the subject.
  • HGF hepatocyte growth factor
  • the action is administering the heparin therapeutic at a specific dose. In some embodiments, the action is administering the heparin therapeutic at a dose within a predetermined range. In some embodiments, the action is withholding administration of the heparin therapeutic.
  • the heparin is a LMWH. In some embodiments, the heparin is M402. In some embodiments, the subject is receiving a therapeutic regimen comprising one or more chemotherapeutic agents. In some embodiments, the subject is receiving a therapeutic regimen comprising gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a heparin, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising a LMWH, gemcitabine and/or nab-paclitaxel. In some embodiments, the subject is receiving a therapeutic regimen comprising M402, gemcitabine and/or nab-paclitaxel.
  • using the information to select an action for the therapeutic regimen comprises: if the level of the HGF provided by the information meets a first
  • the information meets the first
  • predetermined criterion if the level of HGF falls within a predetermined range. In some embodiments, the information meets the first predetermined criterion if the level of HGF is at or above a predetermined level. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF does not fall within a predetermined range. In some embodiments, the information does not meet the first predetermined criterion if the level of HGF is below a predetermined level.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer.
  • the level of HGF is determined in a biological sample obtained from the subject.
  • the biological sample is plasma, serum urine, or whole blood.
  • the level of HGF is determined using an assay selected from the group consisting of: an enzyme-linked immunosorbent assay (ELISA); an aptamer based assay; a microarray; a radioimmunoassay (RIA), an immunofluorescent assay, Western blotting, immunohistochemistry (IHC), immunodiffusion (single or double), Immunoelectrophoresis, or electrophoresis.
  • ELISA enzyme-linked immunosorbent assay
  • aptamer based assay a microarray
  • RIA radioimmunoassay
  • IHC immunohistochemistry
  • IHC immunodiffusion
  • Immunoelectrophoresis or electrophoresis.
  • FIG. 1 shows the dose dependent release of HGF with M402.
  • Plasma samples were obtained from metastatic pancreatic cancer patients across 7 different cohorts in a Phase 1 clinical trial, receiving daily doses of 0.5, 1, 2, 4, 5, or 6 mg/kg M402 in combination with gemcitabine and nab-paclitaxel (4-5 patients per cohort).
  • Plasma samples were obtained at 0, 2, 4, 6, and 8 hours post single dose of M402.
  • HGF was measured in the plasma by ELISA.
  • the line graph shows increased release of HGF following increased doses of M402.
  • the present disclosure provides methods of controlling therapeutic regimens for cancers using HGF as a biomarker of treatment.
  • methods disclosed herein can utilize an assessment of the level of HGF in a subject receiving a therapeutic regimen for a solid tumor cancer to determine and implement changes in the therapeutic regimen.
  • the disclosure is based, in part, on the discovery that the level of HGF is a signal of activity of heparin therapeutics in the treatment of solid tumor cancers.
  • a heparin preparation is a preparation which contains heparin or a preparation derived therefrom.
  • Heparin preparations include unfractionated heparin preparations, low molecular weight heparin (LMWH) preparations, ultra low molecular weight heparin (ULMWH) preparations and the like.
  • LMWH low molecular weight heparin
  • ULMWH ultra low molecular weight heparin
  • UFH unfractionated heparin
  • UFH is heparin purified from porcine intestinal mucosa.
  • UFH can be used, e.g., as a starting material in the process to form a LMWH or an ULMWH.
  • UFH is commercially available from several vendors including Abbott, Organon, Riker, Invenex, Baxter, Calbiochem, Sigma or Upjohn.
  • LMWH preparations include, but are not limited to, an enoxaparin preparation (LovenoxTM or ClexaneTM); a dalteparin preparation (FragminTM); a certoparin preparation (SandoparinTM or Embollex); an ardeparin preparation (NormifloTM); a nadroparin preparation (FraxiparinTM); a parnaparin preparation (FluxumTM); a reviparin preparation (ClivarinTM); a tinzaparin preparation (InnohepTM or LogiparinTM), a fondaparinux preparation (ArixtraTM), or a Ml 18-REH preparation.
  • the LMWH is a LMWH other than an enoxaparin preparation (LovenoxTM or ClexaneTM); a dalteparin preparation
  • the LMWH is described in US8,592,393; US8,569,262; US7,790,700; US7,781,416; US8,222,231 ; US8,067,555; US5,767,269; US5,763,427; US5,744,457;
  • the disclosed LMWHs include glycol split LMWH preparations designed to lack substantial anticoagulant activity while retaining clinically advantageous properties.
  • Properties of the glycol split LMWH preparations include, e.g., lacking substantial anticoagulant activity, e.g., anti-IIa activity less than 50 IU/mg (e.g., anti-IIa activity less than 1 IU/mg), anti-Xa activity less than 50 IU/mg (e.g., anti-Xa activity less than 10 IU/mg), and having anti- metastatic, anti- angiogenic, anti-fibrotic and/or anti-inflammatory activity.
  • the LMWH preparation comprises at least one chain having a glycol split uronic acid residue (UG) and, e g., the preparation can lack substantial anticoagulant activity (e.g., preparations of polysaccharides that have reduced anticoagulant activity) but retain activity in other non-coagulation mediated biological processes.
  • UG glycol split uronic acid residue
  • these LMWH preparations can have one or more of the following features: 1) anti-Xa activity, e.g., less than 50 IU/mg, 20 IU/mg, 10 IU/mg, 5 IU/mg, 3 IU/mg, 2 IU/mg, 1 IU/mg or less, 2) anti-IIa activity, e.g., less than 50 IU/mg, 20 IU/mg, 10 IU/mg, 5 IU/mg, 3 IU/mg, 2 IU/mg, 1 IU/mg or less and 3) anti-metastatic, anti- angiogenic, anti-fibrotic and/or anti-inflammatory activity.
  • anti-Xa activity e.g., less than 50 IU/mg, 20 IU/mg, 10 IU/mg, 5 IU/mg, 3 IU/mg, 2 IU/mg, 1 IU/mg or less
  • anti-IIa activity e.g.
  • a LMWH preparation provided herein can also have one or more of the following characteristics: the preparation has glycol split uronic acid residues (UG) (e.g., less than 50%, 40%, 30%, 20% glycol split uronic acid residues (UG)); the preparation has no more than 3 glycol split uronic acid residues (UG) per polysaccharide chain; the preparation has greater than 40% U 2 sH N s,6s disaccharide residues present in the chains of the preparation; the degree of desulfation of the preparation is less than 40%; one or more polysaccharide chains in the preparation have a 2,5-anhydromannitol residue at the reducing end.
  • UG glycol split uronic acid residues
  • UG glycol split uronic acid residues
  • the weight average molecular weight of the preparation is between 3,500 and 8,000 Da, e.g., between 4,000 and 8,000 Da; and a molecular weight distribution such that 10- 50% (e.g., 10-40%, 10-30%, 15-30% or 15-25%) of the oligosaccharides of the preparation have a molecular weight ⁇ 3000 Da; 40-65% (e.g., 40-60%, 45-65%, 50-65%, or 55-65%) of the oligosaccharides have a molecular weight between 3000-8000 Da, and 5-30% (e.g., 10-30%, 15- 30%, 10-25%, or 15-25%) of the oligosaccharides have a molecular weight > 8000 Da.
  • the LMWH preparation has a weight average molecular weight between 6,000 and 15,000 Da, e.g., between 10,000 and 14,000 Da. In other embodiments, the preparation has a weight average molecular weight between 3,000 and 8,000 Da.
  • Certain embodiments include a LMWH preparation having the following characteristics: (a) a weight average molecular weight between 3,500 and 8,000 Da, e.g., a weight average molecular weight described herein; (b) anti-Xa activity and/or anti-IIa activity, e.g., less than 50 IU/mg (e.g., anti-Xa activity less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 15 IU/mg,
  • the preparation contains between 5% and 50% glycol split uronic acid residues (e.g., between 5% and 40%, 5% and 30%, 10% and 50%, 10% and 40%, 10% and 30%, or 10 and 20% glycol split uronic acid residues).
  • glycol split uronic acid residues e.g., between 5% and 40%, 5% and 30%, 10% and 50%, 10% and 40%, 10% and 30%, or 10 and 20% glycol split uronic acid residues.
  • the preparation has a molecular weight distribution such that 10-50% (e.g., 10-40%, 10-30%, 15-30% or 15-25%) of the oligosaccharides of the preparation have a molecular weight ⁇ 3000 Da; 40-65% (e.g., 40-60%, 45-65%, 50-65%, or 55-65%) of the oligosaccharides have a molecular weight between 3000- 8000 Da, and 5-30% (e.g., 10-30%, 15-30%, 10-25%, or 15-25%) of the oligosaccharides have a molecular weight > 8000 Da.
  • Certain embodiments include a LMWH preparation having the following characteristics: (a) a weight average chain molecular weight between 3,500 and 8,000 Da; (b) anti-Xa activity of less than 20 IU/mg and anti-IIa activity of less than 20 IU/mg; and (c) greater than 5% and less than 25%, e.g., less than 20, less than 10, glycol split uronic acid residues.
  • Certain embodiments include a LMWH preparation having the following characteristics: (a) a weight average chain molecular weight between 3,500 and 8,000 Da; (b) anti-Xa activity of less than 20 IU/mg and anti-IIa activity of less than 20 IU/mg; and (c) greater than 5% and less than 25%, e.g., less than 20, less than 10, glycol split uronic acid residues; wherein the preparation has polysaccharide chains of the preparation having greater than 40%, e.g., greater than 50%, 60%,70%, U 2 SHNS , 6S disaccharide residues within the chains of the preparation.
  • the LMWH preparation has one or more chains having a glycol split uronic acid residue and each polysaccharide chain of the preparation having no more than 3, e.g., no more than 2, no more than 1, glycol split uronic acid residues (UG).
  • UG glycol split uronic acid residues
  • the LMWH preparation has one or more chain having a glycol split uronic acid residue and each polysaccharide chain of the preparation having no more than 2 glycol split uronic acid residues (UG). In some embodiments, the LMWH preparation has one or more chains having a glycol split uronic acid residue and each polysaccharide chain of the preparation having no more than 1 glycol split uronic acid residues (UG).
  • the LMWH preparation preparation has the following
  • the polysaccharide preparation has a molecular weight distribution such that 10-40% of the oligosaccharides of the preparation have a molecular weight ⁇ 3000 Da; 45-65% of the oligosaccharides have a molecular weight between 3000-8000 Da, and 15-30% of the
  • the LMWH preparation comprises a polysaccharide of Formula (I)
  • each X is independently H or S0 3 Y;
  • each X' is independently COCH 3 or S0 3 Y;
  • each Y is independently a singularly charged cation such as Na + , K + , or NH 4 + ;
  • n is an integer from 5 to 14, e.g., 6 to 12;
  • n' is 1, 2 or 3, e.g., 1 or 2;
  • each Y is independently a singularly charged cation such as Na + , K + , or NH 4 + .
  • the polysaccharide of Formula (I) is a polysaccharide of Formula
  • Y for each occurrence is Na + .
  • R is, In some embodiments, the polysaccharide of Formula (I) is a polysaccharide of Formula
  • NNHHSS00 33 NNaa OOHH OOHH NNHHCCOOCCHH, 3 OOHH OOHH NNHHCCOOCCHH 33 OS0 3 Y
  • Y for each occurrence is Na + .
  • R is,
  • the preparation consists essentially of polysaccharides having the structure of Formula (I) or Formula (la) or Formula (lb). In some embodiments, the preparation consists of polysaccharides having the structure of Formula (I) or Formula (la) or Formula (lb).
  • At least about 20% e.g., at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%
  • at least about 20% e.g., at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%
  • the polysaccharides in the preparation have the structure of Formula (I) or Formula (la).
  • the preparation has anti-Xa activity of less than 50 IU/mg, 40 IU/mg, 30 IU/mg, 20 IU/mg or 10 IU/mg but greater than 0.5 IU/mg, 1 IU/mg and/or anti-IIa activity of less than 50 IU/mg, 40 IU/mg, 30 IU/mg, 20 IU/mg or 10 IU/mg but greater than 0.5 IU/mg, 1 IU/mg.
  • the preparation has a weight average chain molecular weight between 3,500 and 8,000 Da, e.g., between 4,000 and 8000 Da, 4,500 and 8,000 Da, 4,700 and 8,000 Da and 5,000 and 8,000 Da.
  • the preparation has a molecular weight distribution such that 10-50% (e.g., 10-40%, 10-30%, 15-30% or 15-25%) of the oligosaccharides of the preparation have a molecular weight ⁇ 3000 Da; 40-65% (e.g., 40-60%, 45-65%, 50-65%, or 55-65%) of the oligosaccharides have a molecular weight between 3000- 8000 Da, and 5-30% (e.g., 10-30%, 15-30%, 10-25%, or 15-25%) of the oligosaccharides have a molecular weight > 8000 Da.
  • the LMWH preparations described herein can also be a pharmaceutically acceptable salt of any of the LMWH preparations described herein.
  • any of the preparations described herein, e.g., described above, can have other properties.
  • one of the above described preparations can further have one or more of the functional or structural properties set out below:
  • the preparation or pharmaceutical preparation has a molecular weight distribution such that 10-50% (e.g., 10-40%, 10-30%, 15-30% or 15-25%) of the oligosaccharides of the preparation have a molecular weight ⁇ 3000 Da; 40-65% (e.g., 40-60%, 45-65%, 50-65%, or 55- 65%) of the oligosaccharides have a molecular weight between 3000-8000 Da, and 5-30% (e.g., 10-30%, 15-30%, 10-25%, or 15-25%) of the oligosaccharides have a molecular weight > 8000 Da; the preparation has a polydispersity of about 1.2 to 1.7 (e.g., about 1.3 to 1.7, 1.4 to 1.6, or 1.3 to 1.6); the preparation has a polydispersity of about 1.2 to 1.8 (e.g., about 1.3 to 1.8, 1.4 to 1.7, or 1.3 to 1.7); the preparation or preparation has a sodium content less
  • the preparation or preparation comprises: less than 20 ppm, 15 ppm, 10 ppm, 5 ppm iodine; less than 30%, 25%, 20%, 15%, 10% sulfur; less than 50, 40, 30, 20, 15 ppm boron; the preparation or preparation has anti-metastatic activity; the preparation or preparation binds specifically to or inhibits an activity of one or more of: VEGF, FGF, SDF- 1- ⁇ , HB-EGF, heparanase, SCF, sonic hedgehog, osteopontin, osteopontegerin or P-selectin.
  • LMWH preparations are disclosed herein that provide substantially reduced anti-IIa activity, e.g., anti-IIa activity of about less than about 50 IU/mg, less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 15 IU/mg, 10 IU/mg, 5 IU/mg, 4 IU/mg, 3 IU/mg, 2 IU/mg , 1 IU/mg or less; or from about 0 to 50 IU/mg, about 0 to 40 IU/mg, about 0 to 30 IU/mg, about 0 to 25 IU/mg, about 0 to 20 IU/mg, about 0 to 10 IU/mg, about 0 to 5 IU/mg, about 5 to 10 IU/mg, about 5 to 15 IU/mg, or about 5 to 20 IU/mg).
  • Anti-IIa activity is calculated in International Units of anti- IIa activity per milligram
  • Anti-factor Ila activity is determined by the sample potentiating effect on antithrombin (ATIII) in the inhibition of thrombin. Thrombin excess can be indirectly spectrophotometrically measured.
  • the anti-factor Ila activity can be measured, e.g., on a Diagnostica Stago analyzer or on an ACL Futura3 Coagulation system, with reagents from Chromogenix (S-2238 substrate, Thrombin (53 nkat/vial), and Antithrombin), or on any equivalent system. Analyzer response is calibrated using the 2nd International Standard for Low Molecular Weight Heparin.
  • a LMWH preparation provided herein has anti-Xa activity of less than about 50 IU/mg, less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 15 IU/mg, 10 IU/mg, 5 IU/mg, 4 IU/mg, 3 IU/mg, 2 IU/mg ,1 IU/mg or less, or about 0 to 50 IU/mg, e.g., 50 IU/mg, 40 IU/mg, 30 IU/mg, 20 IU/mg, 15 IU/mg, 10 IU/mg, 5 IU/mg, 4 IU/mg, 3 IU/mg, 2 IU/mg or 1 IU/mg; or from about 0 to 50 IU/mg, about 0 to 40 IU/mg, about 0 to 30 IU/mg, about 0 to 25 IU/mg, about 0 to 20 IU/mg,
  • a LMWH preparation provided herein has anti-Xa activity of about 2 IU/mg.
  • Anti-Xa activity of a preparation is calculated in International Units of anti-factor Xa activity per milligram using statistical methods for parallel line assays.
  • the anti-factor Xa activity of preparations described herein is measured using the following principle:
  • Antithrombin in the inhibition of activated Factor Xa (FXa).
  • Factor Xa excess can be indirectly spectrophotometrically measured.
  • Anti-factor Xa activity can be measured, e.g., on a Diagnostica Stago analyzer with the Stachrom® Heparin Test kit, on an ACL Futura3
  • Coagulation system with the Coatest® Heparin Kit from Chromogenix, or on any equivalent system.
  • Analyzer response can be calibrated using the NIBSC International Standard for Low Molecular Weight Heparin.
  • LMWH preparations included in the pharmaceutical compositions can have a weight average molecular weight described herein.
  • Weight average molecular weight refers to the weight average in daltons of chains of uronic acid/hexos amine disaccharide repeats.
  • Ci is the concentration of the polymer in slice i
  • mi is the molecular weight of the polymer in slice i.
  • the summations are taken over a chromatographic peak, which contains many slices of data. A slice of data can be pictured as a vertical line on a plot of chromatographic peak versus time. The elution peak can therefore be divided into many slices.
  • the weight average molecular weight calculation is average dependent on the summation of all slices of the concentration and molecular weight.
  • the weight average molar weight can be measured, e.g., using the Wyatt Astra software or any appropriate software.
  • the weight average molecular weights described herein are determined by high liquid chromatography with two columns in series, for example a TSK G3000 SWXL and a G2000 SWXL, coupled with a UV or multi angle light scattering (MALS) detector and a refractometric detector in series.
  • the eluent used is a 0.2 M sodium sulfate, pH 5.0, and a flow rate of 0.5 mL/min.
  • a determination of whether a LMWH preparation includes chains of sufficient chain length can be made, for example, by determining the average chain length of the chains in the preparation and/or by determining the weight average molecular weight of chains within the preparation. For example, when weight average molecular weight of a preparation is
  • a weight average molecular weight of about 3500 to 8000 Da, about 4000 to 8000 Da, about 4200 to 8000, or about 4500 to 8000 Da indicates that a significant number of chains in the LMWH preparation are of a chain length described herein, e.g., for M402, n + n' has an average chain length of 7 to 14.
  • Average chain length refers to the average chain length of uronic acid/hexos amine disaccharide repeats that occur within a chain. Average chain length is determined by dividing the number average molecular weight (Mn) by the number average molecular weight for a disaccharide (500 Da).
  • the molecular weight distribution of a LMWH preparation described herein can be determined by known methods.
  • a LMWH preparation described herein has a molecular weight distribution such that 10-50% (e.g., 10-40%, 10-30%, 15-30% or 15-25%) of the
  • oligosaccharides of the preparation have a molecular weight ⁇ 3000 Da; 40-65% (e.g., 40-60%, 45-65%, 50-65%, or 55-65%) of the oligosaccharides have a molecular weight between 3000- 8000 Da, and 5-30% (e.g., 10-30%, 15-30%, 10-25%, or 15-25%) of the oligosaccharides have a molecular weight > 8000 Da.
  • a LMWH preparation described herein has a molecular weight distribution such that 10-40% of the oligosaccharides of the preparation have a molecular weight ⁇ 3000 Da; 45-65% of the oligosaccharides have a molecular weight between 3000-8000 Da, and 15-30% of the oligosaccharides have a molecular weight > 8000 Da.
  • a LMWH preparation described herein can include an opening of a glycoside ring, conventionally called reduction-oxidation (RO) derivative.
  • RO reduction-oxidation
  • the compounds referred to herein will also be called "Glycol Split" derivatives.
  • glycol split residues lend themselves to the subsequent functionalization. Therefore, polysaccharides of the preparation may also bear equal or different groups, in place of the primary hydroxy groups deriving from glycol split, for example, aldehyde groups, methoxy groups, or oligosaccharide or peptide groups, ranging from a single saccharide or amino acid to more than one unit of length, e.g., 2 or 3 units.
  • fewer than 50% of the total uronic acid residues are glycol split uronic acid residues (e.g., less than 40%, 30%, 25%, or 20% of the total uronic acid residues are glycol split uronic acid residues, e.g., but more than 1%, 2%, 3%, 5% of the total uronic acid residues are glycol split uronic acid residues).
  • At least about 50% of the chains in a LMWH preparation described herein have a modified reducing end structure such as a 2,5-anhydromannose residue or a 2,5- anhydromannose that has been reduced to form an alcohol.
  • at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the chains in the preparation have a modified reducing end structure, such that the reducing end includes a 2,5-anhydromannose residue or a 2,5-anhydromannitol.
  • At least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the chains of a LMWH preparation described herein have a uronic acid at the non- reducing end. In some embodiments, at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the chains of a LMWH preparation described herein have a non native uronic acid at the non-reducing end. In some embodiments, at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the chains of a LMWH preparation described herein have a glycol split uronic acid at the non-reducing end. In some embodiments, the non reducing end of chains of the LMWH preparation has one or more the following structure:
  • each Y is independently a singularly charged cation such as Na + , K + , or NH 4 + .
  • the non-reducing end of the chains of the LMWH preparation have the following structures:
  • each Y is independently a singularly charged cation such as Na + , K + , or NH 4 + .
  • the non-reducing end of the chains of the LMWH preparation have the following structures:
  • the polydispersity of LMWH preparations provided herein is about 2 or less, e.g., 1.8, 1.7 or less, e.g., about 1.7 or 1.6 to 1.2, about 1.4-1.5, and numbers in between.
  • polydisperse or “polydispersity” refers to the weight average molecular weight of a preparation (Mw) divided by the number average molecular weight (Mn).
  • Mw weight average molecular weight of a preparation
  • Mn number average molecular weight
  • Mn ⁇ ci/( ⁇ ci/mi).
  • ci concentration of the polysaccharide in slice i
  • Mi molecular weight of the polysaccharide in slice i.
  • chromatographic peak which contains many slices of data.
  • a slice of data can be pictured as a vertical line on a plot of chromatographic peak versus time.
  • the elution peak can therefore be divided into many slices.
  • the number average molecular weight is a calculation dependent on the molecular weight and concentration at each slice of data. Methods of determining weight average molecular weight are described above, and were used to determine polydispersity as well.
  • M402 refers to a LMWH having one or more of the following characteristics: (a) a weight average chain molecular weight between 3,500 and 8,000 Da; (b) anti-Xa activity of less than 20 IU/mg and anti-IIa activity of 20 IU/mg or less; (c) greater than 5% and less than 25% glycol split uronic acid residues; and (d) the polysaccharide preparation has a molecular weight distribution such that 10-40% of the oligosaccharides of the preparation have a molecular weight ⁇ 3000 Da; 45-65% of the oligosaccharides have a molecular weight between 3000-8000 Da, and 15-30% of the oligosaccharides have a molecular weight > 8000 Da.
  • the LMWH comprises polysaccharides that comprise Formula I:
  • each occurrence of U indicates a uronic acid residue and each occurrence of H indicates a hexosamine residue;
  • n 1-4;
  • each of w, x, y and z can, independently, be the same or different for each occurrence of [U w -H Xi y iZ ] and each of x, y and z can, independently, be the same or different for each occurrence of [UG-H Xi y iZ ] , wherein
  • n 1-3.
  • the M402 preparation has an anti-Xa activity of less than 15 IU/mg. In some instances, the M402 preparation has an anti-Xa activity of less than 10 IU/mg. In some instances, the M402 preparation has an anti-IIa activity of less than 1 IU/mg.
  • the reducing end further comprises a 2,5-anhydromannitol residue. In some instances, about 50% of the reducing ends comprise a 2,5-anhydromannitol residue. In some instances, the reducing end further comprises a 2,5-anhydromannitol residue.
  • the polysaccharides of the M402 preparation have a uronic acid at the non-reducing end. In some instances, the polysaccharides of the M402 preparation have a non native uronic acid at the non-reducing end. In some instances, the polysaccharides of the M402 preparation have a glycol split uronic acid at the non-reducing end.
  • M402 has greater than 5% and less than 20% glycol split uronic acid residues; or between 10% and 20% glycol split uronic acid residues. In some instances, M402 has one or more chains having a glycol split uronic acid residue and polysaccharide chains of the preparation each having no more than 3 glycol split uronic acid residues (U G ).
  • each polysaccharide chain of the M402 preparation has no more than 2 glycol split uronic acid residues (U G ). In some instances, each polysaccharide chain of the M402 preparation ha greater than 40% U 2 SHNS,6S (e.g., greater than, 70% U 2 SHNS,6S) disaccharide residues. In some instances, M402 has a degree of desulfation less than 40% (e.g., less than 30%, less than 10%.).
  • the M402 preparation has a polydispersity of about 1.2 to 1.7. In some instances, M402 has one or more of a sodium content less than 30% ; less than 20 ppm iodine; less than 30% sulfur; and less than 50 ppm boron.
  • the M402 preparation is Necuparinib.
  • a LMWH preparation can be made, e.g., by known methods, e.g., see US 8,592,393 ; US 8,569,262, the contents of each of which are incorporated by reference either in their entirety or specifically for their disclosure regarding methods for preparing a LMWH and/or M402.
  • Therapeutic agents of a therapeutic regimen described herein can be administered to the subject, in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra- articular, intrasynovial, and intrathecal routes.
  • the therapeutic agent is administered to the subject by intravenous administration, e.g., as a bolus or by continuous infusion over a period of time.
  • the therapeutic agent is administered to the subject by subcutaneous (i.e. beneath the skin) administration.
  • the preparation may be injected using a syringe.
  • a polysaccharide (heparin or LMWH (e.g., M402)) pharmaceutical composition or preparation (e.g., as described herein) can be administered to the subject, in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra- articular, intrasynovial, and intrathecal routes.
  • the polysaccharide preparation is administered to the subject by intravenous administration, e.g., as a bolus or by continuous infusion over a period of time.
  • the polysaccharide preparation is administered to the subject by subcutaneous (i.e. beneath the skin) administration.
  • the preparation may be injected using a syringe.
  • injection devices e.g. the Inject-ease.TM. and Genject.TM. devices
  • injector pens such as the GenPen.TM.
  • needleless devices e.g. MediJector.TM. and BioJector.TM.
  • subcutaneous patch delivery systems e.g. the injection devices, injector pens, needleless devices, and subcutaneous patch delivery systems.
  • a polysaccharide (heparin or LMWH (e.g., M402)) pharmaceutical composition or preparation e.g., as described herein
  • Therapeutic regimens described herein can include a plurality of agents, e.g., therapeutic agents, e.g., administered in combination.
  • Administered "in combination", as used herein means that two (or more) different agents are delivered to the subject during the course of the subject' s treatment, such that the effects of the treatments on the patient overlap at a point in time.
  • the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous" or “concurrent delivery.”
  • the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration.
  • the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment.
  • delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive.
  • the delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
  • the therapeutic regimen comprises administering in combination a polysaccharide (e.g., a heparin, a LMWH, e.g., M402) in combination with one or more additional therapies, e.g., surgery, radiation therapy, or administration of another therapeutic preparation.
  • a polysaccharide e.g., a heparin, a LMWH, e.g., M402
  • the additional therapy may include chemotherapy, e.g., a cytotoxic agent.
  • the additional therapy may include a targeted therapy, e.g. a tyrosine kinase inhibitor, a proteasome inhibitor, a protease inhibitor.
  • the additional therapy may include an anti-inflammatory, anti- angiogenic, anti-fibrotic, or antiproliferative compound, e.g., a steroid, a biologic immunomodulator, a monoclonal antibody, an antibody fragment, an aptamer, an siRNA, an antisense molecule, a fusion protein, a cytokine, a cytokine receptor, a bronchodialator, a statin, an anti-inflammatory agent (e.g. methotrexate), an NSAID.
  • the additional therapy could include combining therapeutics of different classes.
  • the polysaccharide preparation and the additional therapy can be administered simultaneously or sequentially.
  • cytotoxic agents that can be administered in combination with the
  • polysaccharide preparation include antimicrotubule agents, topoisomerase inhibitors, antimetabolites, protein synthesis and degradation inhibitors, mitotic inhibitors, alkylating agents, platinating agents, inhibitors of nucleic acid synthesis, histone deacetylase and DNA methyltransferase inhibitors, nitrogen mustards, nitrosoureas, ethylenimines, alkyl sulfonates, triazenes, folate analogs, nucleoside analogs, ribnucleotide reductase inhibitors, vinca alkaloids, taxanes, epothilones, intercalating agents, agents capable of interfering with a signal transduction pathway, agents that promote apoptosis and radiation, antibody conjugates that bind surface proteins to deliver a toxic agent.
  • the cytotoxic agent that can be
  • a platinum-based agent such as cisplatin
  • cyclophosphamide dacarbazine,, methotrexate, fluorouracil, gemcitabine, capecitabine, hydroxyurea, topotecan, irinotecan, azacytidine, vorinostat, ixabepilone, bortezomib, taxanes (paclitaxel, docetaxel), cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, vinorelbine, colchicin, anthracyclines (doxorubicin, epirubicin, daunorubicin), dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, adriamycin, 1-dehydrotestosterone,
  • a platinum-based agent such
  • the combination therapy can also include a polysaccharide described herein
  • one or more additional therapeutic agents e.g., one or more anti-cancer agents, cytotoxic or cytostatic agents, hormone treatment, small molecule inhibitors of receptor tyrosine kinases and other tyrosine kinases including HER-2, EGFR, VEGFR, BCR-ABL, c-KIT (such as Gefitinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Imatinib, Dasatinib, Nilotinib) or mTOR (such as temsirolimus, everolimus, rapamycin), or cytokines or chemokines, vaccines, antibodies against cell membrane receptors pathways including EGF-EGFR, VEGF- VEGFR, CD 19, CD20, CD3, CTLA-4 (such as Trastuzumab, Cetuximab, Panitumumab, Bevacizumab, Rit
  • the polysaccharide is administered in combination with a nucleoside analog.
  • the nucleoside analog is gemcitabine.
  • the heparin is administered in combination with a nucleoside analog and a taxane.
  • the taxane is nab-paclitaxel.
  • the polysaccharide is administered in combination with gemcitabine and nab-paclitaxel.
  • Therapeutic regimens described herein can include one or more therapeutic agents administered to a subject.
  • the dose and dosing regimen of each therapeutic agent of a dosing regimen can be determined by one of skill.
  • the appropriate dosage ("therapeutically effective amount") and regimen of each therapeutic agent will depend, for example, on the condition to be treated, the severity and course of the condition, previous therapy, the patient's clinical history, the type of treatment used, and the discretion of the attending physician. Exemplary dosing and dosing regimens are provided below but should not be construed as limiting.
  • a therapeutic agent can be administered at a dose known in the art for the specific treatment.
  • the treatment can be administered at a dose that is the standard of care for the specific agent when treating a specific condition, e.g., the standard of care at the time the cancer treatment is to be administered.
  • the treatment is a chemotherapeutic agent administered at an amount known in the art for the chemotherapeutic agent.
  • the therapeutic agent is gemcitabine administered at a dose known in the art for gemcitabine. In some embodiments, the therapeutic agent is gemcitabine administered at a dose that is the stanard of care for treating a specific condition, e.g., pancreatic cancer, e.g., the standard of care at the time gemcitabine is to be administered. In certain embodiments, the therapeutic agent is gemcitabine administered at a dose between 500mg/m and 1500mg/m . In certain embodiments, the therapeutic agent is gemcitabine administered at a
  • the therapeutic agent is gemcitabine and is administered at a dose of about lOOOmg/m .
  • the therapeutic agent is nab-paclitaxel administered at a dose known in the art for nab-paclitaxel. In certain embodiments, the therapeutic agent is nab-paclitaxel
  • paclitaxel administered at a dose between 50 mg/m and 300 mg/m .
  • the dose between 50 mg/m and 300 mg/m .
  • the therapeutic agent is nab-paclitaxel administered at a dose of about 260mg/m , lOOmg/m , or 125mg/m .
  • the therapeutic agent is nab-paclitaxel and is administered at
  • a dose of about lOOOmg/m a dose of about lOOOmg/m .
  • a therapeutic agent e.g., a chemotherapeutic agent
  • the therapeutic agent e.g., the chemotherapeutic agent
  • the therapeutic agent e.g., the chemotherapeutic agent
  • the therapeutic agent e.g., the chemotherapeutic agent
  • the therapeutic agent e.g., the chemotherapeutic agent
  • the therapeutic agent can be administered weekly, e.g., once weekly.
  • the therapeutic agent e.g., the chemotherapeutic agent
  • the therapeutic agent can be administered monthly, e.g., once monthly.
  • the therapeutic agent e.g., the chemotherapeutic agent
  • the therapeutic agent (e.g., the chemotherapeutic agent) can be administered every three months, e.g., once every three months.
  • More than one dose (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses) of the therapeutic agent (e.g., the chemotherapeutic agent), can be administered to the subject.
  • the therapeutic agent e.g., the chemotherapeutic agent
  • the therapeutic agent e.g., the chemotherapeutic agent
  • the therapeutic agent e.g., the chemotherapeutic agent
  • the therapeutic agent e.g., the chemotherapeutic agent
  • a polysaccharide described herein e.g., LMWH (e.g., M402)
  • LMWH e.g., M402
  • a dose from 0.5 to 40mg/kg (e.g., l-20mg/kg, 1- lOmg/kg, 0.5- 10mg/kg, 0.5-6mg/kg, 0.5-5mg/kg, l-5mg/kg, 2-9mg/kg, 3-8mg/kg 3-5mg/kg).
  • the LMWH (e.g., M402), can be administered at a dose of lmg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, or lOmg/kg.
  • the LMWH e.g., M402
  • the LMWH is administered at a dose of lmg/kg.
  • the LMWH (e.g., M402)
  • the LMWH (e.g., M402)
  • the LMWH (e.g., M402), is administered at a dose of 4mg/kg. In some embodiments, the LMWH (e.g., M402), is administered at a dose of 5mg/kg. In some embodiments, the LMWH (e.g., M402), is administered at a dose of 6mg/kg. In some embodiments.
  • a polysaccharide described herein can be administered daily (e.g., once daily, twice daily), weekly, every other week, every three weeks, monthly, every other month, or every three months.
  • the LMWH e.g., M402
  • the LMWH can be administered daily, e.g., once daily.
  • the LMWH e.g., M402
  • the LMWH can be administered weekly, e.g., once weekly.
  • the LMWH (e.g., M402) can be administered monthly, e.g., once monthly.
  • the LMWH (e.g., M402) can be administered every other month monthly, e.g., once every other monthly.
  • the LMWH (e.g., M402), can be administered every three months, e.g., once every three months.
  • the LMWH (e.g., M402) is administered once daily.
  • the LMWH (e.g., M402) can be administered daily (e.g., once daily, twice daily), weekly, every other week, every three weeks, monthly, every other month, or every three months for a period of at least 1 week (e.g., at least 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year).
  • the LMWH (e.g., M402), can be administered daily, e.g., once daily, for a period of at least 1 week (e.g., at least 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year).
  • the LMWH (e.g., M402), can be administered weekly, e.g., once weekly, for a period of at least 1 week (e.g., at least 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year).
  • the polysaccharide e.g., LMWH (e.g., M402)
  • LMWH e.g., M402
  • more than one dose e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses
  • the LMWH e.g., M402
  • the therapeutic regimen comprises a heparin (e.g., M402) administered daily at a dose of 0.5-6mg/kg; and gemcitabine administered at a dose of 50- 2000mg/m on days 1, 8, and 15 of each of a 28 day cycle.
  • a heparin e.g., M402
  • gemcitabine administered at a dose of 50- 2000mg/m on days 1, 8, and 15 of each of a 28 day cycle.
  • the therapeutic regimen comprises a heparin (e.g., M402) administered daily at a dose of 0.5-6mg/kg; and gemcitabine administered at a dose of 50- 2000mg/m on days 1, 8, and 15 of each of a 28 day cycle, and nab-paclitaxel administered at a dose of 50-2000mg/m on days 1, 8, and 15 of each of a 28 day cycle.
  • a heparin e.g., M402
  • gemcitabine administered at a dose of 50- 2000mg/m on days 1, 8, and 15 of each of a 28 day cycle
  • nab-paclitaxel administered at a dose of 50-2000mg/m on days 1, 8, and 15 of each of a 28 day cycle.
  • the therapeutic regimen comprises a heparin (e.g., M402) administered daily at a dose of about 5mg/kg; and gemcitabine administered at a dose of 1000mg/m on days 1, 8, and 15 of each of a 28 day cycle.
  • a heparin e.g., M402
  • gemcitabine administered at a dose of 1000mg/m on days 1, 8, and 15 of each of a 28 day cycle.
  • the therapeutic regimen comprises a heparin (e.g., M402) administered daily at a dose of about 5mg/kg; gemcitabine administered at a dose of
  • the therapeutic regimen comprises a heparin (e.g., M402) administered daily at a dose of about 5mg/kg; gemcitabine administered once a week for the first 7 weeks at a dose of lOOOmg/m ; followed by one week with no administration; followed by administration once a week for 3 weeks at a dose of lOOOmg/m and no administration for one week of a 28 day cycle.
  • a heparin e.g., M402
  • gemcitabine administered once a week for the first 7 weeks at a dose of lOOOmg/m ; followed by one week with no administration; followed by administration once a week for 3 weeks at a dose of lOOOmg/m and no administration for one week of a 28 day cycle.
  • the therapeutic regimen comprises a heparin (e.g., M402) administered daily at a dose of about 5mg/kg; gemcitabine administered at a dose of lOOOmg/m on days 1, 8, and 15 of each of a 21 day cycle.
  • a heparin e.g., M402
  • gemcitabine administered at a dose of lOOOmg/m on days 1, 8, and 15 of each of a 21 day cycle.
  • the therapeutic regimen comprises a heparin (e.g., M402) administered daily at a dose of about 5mg/kg; gemcitabine administered at a dose of lOOOmg/m on days 1, 8, and 15 of each of a 21 day cycle.
  • a heparin e.g., M402
  • gemcitabine administered at a dose of lOOOmg/m on days 1, 8, and 15 of each of a 21 day cycle.
  • the therapeutic regimen comprises a heparin (e.g., M402) administered at an approved dose for the heparin (e.g., M402); gemcitabine administered at an approved dose for gemcitabine, and nab-paclitaxel administered at an approved dose for nab- paclitaxel.
  • a heparin e.g., M402
  • gemcitabine administered at an approved dose for gemcitabine
  • nab-paclitaxel administered at an approved dose for nab- paclitaxel.
  • the subject is receiving a therapeutic regimen, e.g., a therapeutic regimen comprising a heparin.
  • the subject is receiving a therapeutic regimen described herein, e.g., a therapeutic regimen comprising a heparin described herein.
  • the subject is receiving a therapeutic regimen, e.g., a therapeutic regimen comprising M402.
  • the subject is receiving a therapeutic regimen, e.g., a therapeutic regimen comprising M402 and one or more chemotherapeutic agent described herein, e.g., gemcitabine and optionally nab-paclitaxel.
  • the subject is a candidate to receive a therapeutic regimen, e.g., a therapeutic regimen comprising a heparin.
  • the subject is a candidate to receive a therapeutic regimen described herein, e.g., a therapeutic regimen comprising a heparin described herein.
  • the subject is a candidate to receive a therapeutic regimen, e.g., a therapeutic regimen comprising M402.
  • the subject is a candidate to receive a therapeutic regimen, e.g., a therapeutic regimen comprising M402 and one or more chemotherapeutic agent described herein, e.g., gemcitabine and optionally nab- paclitaxel.
  • the subject has been diagnosed with a metastatic cancer described herein. In some embodiments, the subject has been diagnosed with a solid tumor cancer.
  • compositions described herein can be used to treat a subject.
  • a subject is a human.
  • compositions provided herein can be used, for example, to treat or prevent a cancer (e.g., a cancer, e.g., a carcinoma or other solid or hematological cancer, a cancer metastases) in a subject.
  • a cancer e.g., a cancer, e.g., a carcinoma or other solid or hematological cancer, a cancer metastases
  • cancer is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. Methods and compositions disclosed herein are particularly useful for treating, or reducing the size, numbers, or rate of growth of, metastatic lesions associated with cancer.
  • the cancer is a solid tumor cancer, e.g., sarcomas, carcinomas, and lymphomas. In some embodiments the cancer is a sarcoma. In some embodiments the cancer is a carcinoma, in some embodiments the cancer is a lymphoma. In some embodiments, the cancer is a solid tumor cancer selected from the group consisting of pancreatic cancer, breast cancer (e.g., triple negative breast cancer, inflammatory breast cancer), esophageal cancer, glioma, stomach cancer, lung cancer, and colorectal cancer. In some embodiments the cancer is a metastatic solid tumor cancer.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is breast cancer (e.g., triple negative breast cancer, or inflammatory breast cancer). In some embodiments, the cancer is glioma (e.g., glioblastoma). In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer or small cell lung cancer). In some embodiments, the cancer is colorectal cancer (e.g., colon cancer or rectal cancer).
  • the cancer is a hematological cancer, e.g., a leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL)); a lymphoma (e.g., Hodgkin's lymphoma, Non-Hodgkin's lymphoma).
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • AMOL acute monocytic leukemia
  • a lymphoma e.g., Hodgkin's lymphoma, Non-Hodgkin's lymphoma
  • the cancer is a metastatic cancer. In some embodiments, the cancer is metastatic pancreatic cancer. In some embodiments, the cancer is metastatic esophageal cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is metastatic triple negative breast cancer. In some embodiments, the cancer is metastatic inflammatory breast cancer. In some embodiments, the cancer is metastatic glioma (e.g., metastatic glioblastoma). In some embodiments, the cancer is metastatic stomach cancer. In some embodiments, the cancer is metastatic lung cancer (e.g., metastatic non-small cell lung cancer or metastatic small cell lung cancer). In some embodiments, the cancer is metastatic colorectal cancer (e.g., metastatic colon cancer or metastatic rectal cancer).
  • metastatic pancreatic cancer In some embodiments, the cancer is metastatic esophageal cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is metastatic triple negative breast cancer. In some embodiments,
  • Exemplary breast cancers can include triple negative breast cancer, basal-like breast cancer, claudin-low breast cancer, invasive, inflammatory, metaplastic, and advanced Her-2 positive or ER-positive cancers resistant to therapy.
  • cancers include but are not limited to, renal cancer, liver cancer, thyroid cancer, ovarian cancer; prostate cancer, head and neck cancer, a hematological cancer (e.g., a leukemia, e.g., acute lymphoblastic leukemia, acute myelogenous leukemia, T cell leukemia, multiple myeloma; a lymphoma, e.g., diffuse large B cell lymphoma), a skin cancer (e.g., melanoma, squamous cell carcinoma), brain cancer, abdominal cancer, gastrointestinal cancer, liver cancer, neuroblastoma, osteosarcoma, ovarian cancer, retinoblastoma, retinal cancer, bladder cancer, cervical cancer, endometrial cancer, uterine cancer, nasopharyngeal carcinoma, and testicular cancer.
  • a leukemia e.g., acute lymphoblastic leukemia, acute myelogenous leukemia, T cell leukemia, multiple myel
  • HGF Hepatocyte Growth Factor
  • Hepatocyte Growth Factor HGF
  • Hepapoietin A Scatter Factor
  • F-TCF HGFB
  • HGF Fibroblast-Derived Tumor Cytotoxic Factor
  • Lung Fibroblast-Derived Mitogen Hepatocyte growth factor regulates cell growth, cell motility, and morphogenesis by activating a tyrosine kinase signaling cascade after binding to the proto-oncogenic c-Met receptor.
  • HGF is secreted by mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. HGF has a central role in angiogenesis, tumorogenesis, and tissue regeneration.
  • HGF is secreted as a single inactive polypeptide and is cleaved by serine proteases into a 69-kDa alpha-chain and 34-kDa beta-chain; and a disulfide bond between the alpha and beta chains produces the active, heterodimeric molecule.
  • HGF belongs to the plasminogen subfamily of S 1 peptidases but has no detectable protease activity. Alternative splicing of this gene produces multiple transcript variants encoding different isoforms.
  • HGF amino acid and nucleotide sequences are known in the art. HGF is known in the art to have multiple isoforms. An exemplary amino acid and nucleotide sequence for human HGF are provided herein as SEQ ID NO: 1 and SEQ ID NO: 2, respectively.
  • sample each refers to a biological sample obtained from a tissue or bodily fluid of a subject or patient.
  • the source of the tissue sample can be solid tissue as from a fresh, frozen and/or preserved organ, tissue sample, biopsy, or aspirate; blood or any blood constituents (e.g., serum, plasma); bodily fluids such as urine, cerebral spinal fluid, whole blood, plasma and serum.
  • the sample can include a non-cellular fraction (e.g., urine, plasma, serum, or other non-cellular body fluid).
  • the sample is a urine sample.
  • the body fluid from which the sample is obtained from an individual comprises blood (e.g., whole blood).
  • the sample is a whole blood sample obtained from the subject.
  • the blood can be further processed to obtain plasma or serum.
  • the sample is a serum sample.
  • the sample is a plasma sample.
  • sample includes any material obtained and/or derived from a biological sample, including a polypeptide, and nucleic acid (e.g., genomic DNA, cDNA, RNA) purified or processed from the sample. Purification and/or processing of the sample can involve one or more of extraction, concentration, antibody isolation, sorting, concentration, fixation, addition of reagents and the like.
  • the sample can contain compounds that are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics or the like.
  • the level of HGF can be assessed by any of a wide variety of well known methods for detecting expression of a protein. Non-limiting examples of such methods include
  • Immunoassays which can be used include but are not limited to competitive and noncompetitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, western blot.
  • an ELISA uses a solid-phase enzyme immunoassay (EIA) to detect the presence of a substance, e.g., a protein of interest, in a liquid sample or wet sample.
  • EIA enzyme immunoassay
  • antigens from the sample are attached to a surface.
  • the detection antibody is added, forming a complex with the antigen.
  • the detection antibody can be covalently linked to an enzyme, or can itself be detected by a secondary antibody that is linked to an enzyme through bioconjugation.
  • the plate is typically washed with a mild detergent solution to remove any proteins or antibodies that are non-specifically bound.
  • the plate is developed by adding an enzymatic substrate to produce a visible signal, which indicates the quantity of antigen in the sample.
  • an ELISA known to those of skill in the art include but are not limited to, a sandwich ELISA, a direct ELISA, and competitive ELISA.
  • Nucleic acid aptamers can be used as marker detection reagents. Aptamers are engineered through repeated rounds of in vitro selection or equivalently, SELEX (systematic evolution of ligands by exponential enrichment) to bind to various molecular targets such as small molecules, proteins, nucleic acids. Aptamers can be produced by standard methods known to one of skill in the art. For example, SOMAmerTM (Slow Off-rate Modified Aptamer) aptamers are single stranded DNA -based aptamers which incorporate chemically modified nucleotides that mimic amino acid side chains, enhancing the specificity and affinity of protein-nucleic acid interactions.
  • SOMAmerTM Small Off-rate Modified Aptamer
  • a protein microarray (or protein chip) can be used.
  • a protein microarray can be used to detect the level of HGF and one or more additional proteins in the sample.
  • the chip consists of a support surface such as a glass slide, nitrocellulose membrane, bead, or microtitre plate, to which an array of capture proteins is bound.
  • Probe molecules typically labeled with a fluorescent dye, are added to the array. Any reaction between the probe and the immobilised protein emits a fluorescent signal that is read by a laser scanner. Also described herein are probes capable of binding to HGF.
  • the selection of an action is based on whether the level of HGF meets (e.g., corresponds with, satisfies, or falls within), is greater than, or is less than, a predetermined range (e.g., a range including the minimum and maximum values of the range, and in some cases plus or minus a window of variability (e.g., +/-0.5%, +/- 1%, +1-5%, +/- 10% or +/-20%); or level (e.g., an average value (or other value of central tendency) plus or minus a window of variability (e.g., +1-0.5%, +/-! %, +1-5%, +/-10% or +1-20%)).
  • a predetermined range e.g., a range including the minimum and maximum values of the range, and in some cases plus or minus a window of variability (e.g., +/-0.5%, +/- 1%, +1-5%, +/- 10% or +/-20%)
  • level e.g
  • the level of HGF is expressed as a single value (e.g., an average value (or other value of central tendency) plus or minus a window of variability (e.g., +1-0.5%, +l- ⁇ %, +1-5%, +/- 10% or +1-20%)) and the predetermined level is also expressed as a single value (e.g., an average value (or other value of central tendency) plus or minus a window of variability (e.g., +1-0.5%, +/-1%, +1-5%, +/- 10% or +1-20%)).
  • the level of HGF is expressed as a single value (e.g., an average value (or other value of central tendency) plus or minus a window of variability (e.g., +1-0.5%, +1- 1%, +1-5%, +1- 10% or +1-20%)) and selection of an action is based on whether the level of HGF falls within a certain percentage of (e.g., within 70%- 130%) of the predetermined value.
  • a window of variability e.g., +1-0.5%, +1- 1%, +1-5%, +1- 10% or +1-20%)
  • the level of HGF is expressed as a single value (e.g., an average value (or other value of central tendency) plus or minus a window of variability (e.g., +1-0.5%, +1-1%, +1-5%, +/- 10% or +/-20%)) and selection of an action is based on whether the level of HGF is higher or lower than the predetermined value.
  • a single value e.g., an average value (or other value of central tendency) plus or minus a window of variability (e.g., +1-0.5%, +1-1%, +1-5%, +/- 10% or +/-20%)
  • selection of an action is based on whether the level of HGF is higher or lower than the predetermined value.
  • the level of HGF is expressed as a single value (e.g., an average value (or other value of central tendency) plus or minus a window of variability (e.g., +1-0.5%, +/-1%, +1-5%, +/- 10% or +/-20%)) and the predetermined level is expressed as a range (e.g., a range including the minimum and maximum values of the range, and in some cases plus or minus a window of variability (e.g., +1-0.5%, +1- 1%, +1-5%, +1- 10% or +1-20%)).
  • the level of HGF is expressed as a single value (e.g., an average value (or other value of central tendency) plus or minus a window of variability (e.g., +1-0.5%, +l- ⁇ %, +1-5%, +/- 10% or +/- 20%)) and selection of an action is based on whether the level of HGF falls within a single value (e.g., an average value (or other value of central tendency) plus or minus a window of variability (e.g., +1-0.5%, +l- ⁇ %, +1-5%, +/- 10% or +/- 20%)) and selection of an action is based on whether the level of HGF falls within a window of variability (e.g., +1-0.5%, +l- ⁇ %, +1-5%, +/- 10% or +/- 20%)) and selection of an action is based on whether the level of HGF falls within a window of variability (e.g., +1-0.5%, +l- ⁇ %, +1-5%,
  • predetermined range e.g., a range including the minimum and maximum values of the range, and in some cases plus or minus a window of variability (e.g., +1-0.5%, +l- ⁇ %, +1-5%, +/- 10% or +1-20%)).
  • the predetermined level is the level of HGF in a biological sample obtained from the subject prior to the administration of a reference dose of one or more therapeutic agents in the therapeutic regimen (e.g., prior to the administration of a predetermined dose of the therapeutic agent, prior to the administration of the therapeutic agent, prior to the administration of the most recent dose of the therapeutic agent, prior to the administration of the 2 nd , 3 rd , 4 th , 5 th , 10 th , 20 th , 30 th , 40 th , or 50 th dose of the therapeutic agent).
  • the predetermined range is the level of HGF in a biological sample obtained from the subject prior to the administration of a reference dose of one or more therapeutic agents in the therapeutic regimen (e.g., prior to the administration of a predetermined dose of the therapeutic agent, prior to the administration of the therapeutic agent, prior to the administration of the most recent dose of the therapeutic agent, prior to the administration of the 2 nd , 3 rd , 4 th , 5 th , 10 th , 20 th , 30 th , 40 th , or 50 th dose of the therapeutic agent) and +1-0.5%, +/-! %, +1- 5%, +/- 10% or +/-20%).
  • the action described herein is modifying a therapeutic regimen described herein to increase or decrease the amount of a therapeutic agent in the therapeutic regimen administered to the patient. In some embodiments, the action described herein is maintaining a therapeutic regimen described herein to maintain the amount of a therapeutic agent in the therapeutic regimen administered to the patient. In some embodiments, the action described herein is modifying a therapeutic regimen described herein to permanently discontinue treatment with the therapeutic regimen, or part of the therapeutic regimen. In some embodiments, the action described herein is modifying a therapeutic regimen described herein to withhold one or more doses a therapeutic agent in the regimen. In some embodiments, the action described herein is modifying a therapeutic regimen described herein to add one or more additional therapeutic agent to the therapeutic regimen. In some embodiments, the action described herein is modifying a therapeutic regimen described herein to remove one or more therapeutic agents from the therapeutic regimen.
  • Levels of circulating HGF were evaluated in patients enrolled in phase 1 clinical trial evaluating the use of M402 therapeutic regimens in the treatment of metastatic pancreatic cancer. Assessed patients were across multiple cohorts, wherein the patients were receiving a therapeutic regimen including daily doses of 0.5mg/kg, lmg/kg, 2mg/kg, 4mg/kg, 5mg/kg or 6mg/kg of M402 in combination with gemcitabine and nab-paclitaxel. Plasma samples were obtained 0, 1, 2, 4, 6, 8, and 24 hours post M402 injection, and the level of HGF determined utilizing an HGF ELISA. As shown in FIG.
  • Example 2 Methods of controlling M402 therapeutic regimens utilizing assessment of HGF
  • the level of circulating HGF was found to be M402 dose dependent; suggesting that HGF can be used to direct subsequent action during the course of M402 treatment.
  • the following Example describes methods of controlling M402 therapeutic regimens using the level of circulating HGF in a patient receiving an M402 therapeutic regimen.
  • a patient diagnosed with cancer who is a determined to be a candidate for M402 treatment will have circulating HGF levels assessed prior to the initiation of or concurrent with the initiation of an M402 therapeutic regimen; and subsequently measured at one or more later time points during administration of the M402 regimen.
  • a patient currently receiving an M402 therapeutic regimen will have the level of circulating HGF assessed at one or more later time points during administration of the treatment regimen.
  • the level of HGF at the later time point will be compared to the level of HGF at a previous time point, and used to dictate changes in the M402 treatment regimen, such as increasing or decreasing the dose administered, increasing or decreasing the time between doses, maintaining the dosing regimen, withholding one or more doses, or permanently discontinuing M402 administration.
  • the level of circulating HGF can be evaluated by ELISA prior to the initiation of M402 treatment and after one month of M402 treatment, and the levels of HGF compared. If the level of HGF after one month of treatment is within a specified range compared to the level of HGF prior to treatment the dose may be increased and administered at the increased dose, e.g., 5mg/kg.
  • Example 3 Methods of controlling therapeutic regimens for solid tumor cancers utilizing assessment of HGF
  • Example describes methods of controlling therapeutic regimens for solid tumor cancers using the level of circulating HGF in a patient receiving a therapeutic regimen.
  • a patient diagnosed with a solid tumor cancer who is a determined to be a candidate for a treatment with a specified therapeutic regimen will have circulating HGF levels assessed prior to the initiation of or concurrent with the initiation of the therapeutic regimen; and subsequently measured at one or more later time points during administration of the regimen.
  • a patient currently receiving a therapeutic regimen will have the level of circulating HGF assessed at one or more later time points during administration of the treatment regimen.
  • the level of HGF at the later time point will be compared to the level of HGF at a previous time point, and used to dictate changes in the treatment regimen, such as increasing or decreasing the dose administered, increasing or decreasing the time between doses, maintaining the dosing regimen, withholding one or more doses, or permanently discontinuing heparin administration. For example, if the level of HGF at the later time point is within a specified range that is less than the level of HGF prior to treatment the dose will be increased and administered at the increased dose.

Abstract

L'invention concerne des méthodes de contrôle de régimes thérapeutiques dans lesquelles une évaluation du facteur HGF est effectuée.
PCT/US2016/016133 2015-02-03 2016-02-02 Méthodes de contrôle de régimes thérapeutiques WO2016126682A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140127193A1 (en) * 2011-05-05 2014-05-08 Duke University Methods of developing a prognosis for pancreatic cancer and predicting responsiveness to cancer therapeutics
US20140275073A1 (en) * 2013-03-12 2014-09-18 The Board Of Trustees Of The Leland Stanford Junior University Methods of treating cancer sensitive to anti-egfr therapy and modifying treatment using blood biomarkers
WO2014193818A1 (fr) * 2013-05-28 2014-12-04 Momenta Pharmaceuticals, Inc. Compositions pharmaceutiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140127193A1 (en) * 2011-05-05 2014-05-08 Duke University Methods of developing a prognosis for pancreatic cancer and predicting responsiveness to cancer therapeutics
US20140275073A1 (en) * 2013-03-12 2014-09-18 The Board Of Trustees Of The Leland Stanford Junior University Methods of treating cancer sensitive to anti-egfr therapy and modifying treatment using blood biomarkers
WO2014193818A1 (fr) * 2013-05-28 2014-12-04 Momenta Pharmaceuticals, Inc. Compositions pharmaceutiques

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